Number of patients to develop hemodialysis have been increasing with the deterioration of kidney disease due to chronic diseases such as diabetes, collagen diseases and hypertension. More than about 10,000 patients per year have started a new dialysis. Since the prognosis of hemodialysis patients who have shifted from chronic disease to renal failure is significantly worse than that of other diseases, measures to improve prognosis have been urgently needed. In the early stage of the disease, the inflammatory response plays an important role in the pathogenesis of kidney damage. As the condition progresses, fibrosis occurs by abnormal epithelial and mesenchymal tissue reactions. Many factors including TGFβ1, connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), inflammatory cytokine, chemokine (C—C motif) ligand 2/monocyte chemotactic protein 1 (CCL 2), oxidizing agents and coagulation factors are considered as causes of tissue fibrosis.
TGFβ1 is a major cytokine in the pathogenesis of remodeling, including fibrosis and tissue repair in many organs, including the kidney. Many kinds of cells including macrophages, T cells, eosinophils, neutrophilsng and basophils produce TGFβ1. TGFβ1 is stored in a non-active form that is bound to a related protein (latency-associated protein (LAP)) in a cell. When the non-active TGFβ1 is separated from LAP by cathepsin, plasmin, calpain, thrombospondin, integrin-αvβ6 or metalloproteinase, which increase commonly in the process of fibrosis, activated TGFβ1 is released. According to experiments using genetically modified animals, kidney fibrosis associated with mononuclear cell infiltration is induced, when the active TGFβ1 concentration in the blood rises. TGFβ1 plays an important role in the kidney fibrosis. Meanwhile, active and latent TGFβ1 are observed at high concentrations in the blood, urine and kidney tissues of patients with severe renal fibrosis.
For research on human organ fibrosis and development of drugs related to organ fibrosis, model animals (for example, mouse etc.) expressing human TGFβ1 in a specific organ has been required. The present inventors have been studying human TGFβ1 for many years and succeeded in developing transgenic (TG) mouse expressing human TGFβ1 specifically in lung (Patent Document 1).
However, reports of TG mice expressing human TGFβ1 specifically in the kidney have been not observed. Therefore, there remains a situation in which research on kidney fibrosis has to be conducted using TG mouse expressing human TGFβ1 in other organs including kidney tissue (Non-Patent Document 1).
On the other hand, although a biomarker for a tissue fibrosis mouse model is known (Non-Patent Document 2), the biomarker only indicates the degree of inflammation associated with the process of fibrosis, and is not specific for tissue fibrosis.